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I 1150 SEANFLLD, HOSltitrAGER, MyD At:SS9tLLD hamsters. Approximately half contained only normal adrsnats tissues. The remainder showed various pathologic The most frequent change obsetvr.,, in ci:: 3dr processes including gingivitis, dental caries, ocular of both strains was proliferatiort cf capsuiar inflammation with phthtsis bulbi, and thromboses of orbital veins. None of these phenomena could be This was reported previously in hamotu-• ::l i related to smoke exposure. mice, where it was called "A-8 ce)1 hy}-. „~asa' This proliferation, not affected by smokt e.pc ~On! 2_ ~rumon were found in the nasopharynx, was xen in { 1'~'e of BIO 15.16 and in '100s, ot bot oci eurr~in.g y~$I~~26~sitttais xnRosed to- 87•20 hamsters. Of the BIO 15.16 hau.~sters, i4~ SertoicE•6U-~5 weeks. One was an adenoid cystie tumo ` adrenal adenomas and 1;, carcinomas, as comE be ieve to h`ave o~riginaied?rom mucous glands with 135'a with adenomas and 5% with carcinom (fig`Zl~. Ttfi other tvas "a"fib~d32~com3_thaE2i,zd pro' the BIO 87.20 animals. Rarcly carcinomas t: duced nuastT6ui'"itaall puTiiionary metastases (figs, tasized to the lungs. The occurrence of adrenal ru 22, 23)--••--- was not related to smoke exposure. Of the anim: both strains, 5-10 ; exhibited adrenal amy!oidcs Heart The heart itself was not sectioned routinely in this DISCUSSION I However, it was included with the lungs The model system used 'by us differs frotn of 20-25%, of the animals. Of the cage-held control reported by Dontenwtll et al. l!) and Donten.nf I B1.O 15.16 hearts, 25 ; showed myocardial degenera- in several important respects in addition to our : tion as compared with 1'r, of the BIO 87.20 heartt. inbred hamsters. The composition of the 1R1 b This consisted of myolvsu with (in the 8IO 15.16 tucky reference cigarettes was different than tha animals only) an abundant intiltratron of lymphocytes. Dontenwill's cigarettes. i,4..pQnun;ziUl..iL%.d_v_.- Smoke exposure appeared to increase myocardial de- sters' bodies were enclosed in a tuoe and ::us se~- ¢eneration ;n both strains, especially in the BIO ---s`ff&Ted-. IN-6un e ere-nor.-emokeexpo.uM - 15.16 animals. However, the number of animals epti tnuous tn o~tS 7i11's't t3t`ttttt; "i~terrn: =^' examined waa too small to permit definitive conclu- ours. Concentration of inhaled smoke was about 11 s:ons (data not stacisncally slgnificant)• in the German model and 20cl, in ours, and scr - Mural thrombi were seen in approximately one- was administered by different dosage schedu!es. ftfth of the hearts of both strains. Incidence was not Nonetheless, both model systems permit ,he sa affected by the experimental procedures. major condusioas: Chronic exposure o cigare smoke produces severe hyperplasac and neopla: t.iver changes in the squamous epithelium of :he hams The most frequent abnormality in the livers of larynx and is associated with decreased body weig these hamsters was cystic hyperplasia of the bile ducts, In neither system did smoke esposurL increase pi in rare instances verging on cholangiocarcinoma. This liferative. changes outside the respiratory tract change occurred after the 60th week of the experiment increase the non-neoplastie degenerative chang and was more frcquent in the 8IO 87 20 (60%) than characteristic of aging hamsters. (Our observations ( in the 810 15.16 (I7?r'a) animals. Other abnormalities possible smoke-related changes in the heart 3re pre noted were not strain related and consisted of sporadic ently equivoeal; further investigation is desirable.) intiltration with amyloid and leukemic material, fatty Chronic smoke exposure signi6cantly reduced su metamorphosis, focal inflammation, and focal necrosis. wa1 time in the Dontenwill model; no such erTr One primary hemangiosarcoma of the liver was found was seen in ours. This difference may be attnbute in a csge-held BIO 15.16 control. None of these to the twofold higher carbon monoxide concentratic changes could be related to smoke exposure. inhaled by Dontenwill's haas:ers than by ours. I fact, previous observations of Dontenwill (10) showet Spie1n a sustained increase in blood carboxyhemoglobin in b.: A irnatel three-quarters the s model, whereas ours produced only transient increisa PProx Y -quatten o Pleeru ex- Both systems produced no change in blood triglycer amined in both strains were histologically normal• ides. In addition, we showed no change in vtru: Lesions in the remainder included hemangiomas, profile. lymphotnataus or leuketnic infiltrates, and amyloid. The po int of greatest practical importance to None of these conditions was related to strain or to emerge from otu work is the stnktng differencea arnong smoke exposure. various Lines of hamaters with respect to suxepubilitv to acute toxie effects of smoke and to hyperplasac Kidneys response of the larynx to smoke (3). Animals of the Some renal amyloidosis was seen in 86q', of the inbred BIO 15.16 line have both the higheet resistance BIO 15.16 and 69%, of the BIO dJ 10 hamsters. In to smoke or nicotine toxicity and :he qreatest laryngeal susceptibiliw-qualities greatly :.^.crea.sing the scnsi- r.etther strain was it affected by smoke inhalation. tivity of the model. Further studies w,th larger num- The only other renal pathology consisted of rare, bers of animals will be necessarv to iscertain :he minute foci of calcification in a few hamsten of significance of the laryngeal char:ges in different each strain. strains. .... _.r..- - C T R ~~~~ 0 42~~~

CIGARLTrL 3NOK6 NHALAttOV IN (NHRED HAseSTE0.S ! Ijl No tumon of the lung parenehv;tta aiter___ j SRoke A. Weirihouse s, eda.), vol 8. Sew York, Acade_n~: e`ct)OSure w t'T ontenwill_ or by Presf Inc., 15ti4, Pp 2i9-253 ~ ~~~ 11 BeR~RIO P, HOMRCRC[R F: High n cocine toleraace of uf.~` 'e did not co_ntti tl'lt~h K~, nt.ulcre35e_ __ Svnan golden hamsters. Toxtcol .ippl Pharmacol in a enom-a toad_lesions.obsetved_hv-Dontenw{It. In 22:324. 1972 bo__tl~-ir.odel systems, so-called "smoke cells" increased in the al.eoli after smoke exposure. The observation that %ellow iron•negative and also black particlee occur in the macrophages suggests that the particulate phase of smoke reached the alveolar wall to be taken up by the macrophages. Use of the 2 inbred lines in our experiment permitted the conclusion that these celJs are not directly related to hyperplastic changes in the respiratory tract. They were much more abun- dant in the BlO 87.20 hamsters, which had the lower ncidence of hyperplastic lesions. The tracheal and bronchial papillomas and the nasooharn•ngeal tumors (one with clear•cut metas- •ises) observed in our smoke-exposed hamsters resem- hle tumors induced by others with nitrosamines (11) :nd suggest the presence of this class of substances in ;.-e smoke from our reference cigarettes. The only -itrosamine so far detected in cigarette smoke con• :ensates, however, is dimethytnitrosamine (1?). =EFERENCES 1) Do.rza~itt tt', Cacvaaa H•J, HAARS H•P, et al fn- es::¢a:.ons on 'he et[eeu of chronie uqare::e•er oce n• h.vat:on in Syrnan ;olden huruten J Nad Cancer (^st it Iv73 `1 1V1vocR Ett Horrwwrv D: Expenmental tobacco car- anogenesu. /a .%dvances in Cancer Rexarch (Haddow HorrxA-4>r D, WyxotR EL: Chamber development and aerosol dispersion. In Inhalation Carcinogenes t Hanna \tG Jr, Nettesheim P, Gilbert JR, eds.). .iEC Symp Series No. 18, 1970, pp 173-189 AntLMso. WO: Production of sample c garettes for tobacco and health rexareh. Tobacco and Health Conf, Rept Yo. Z, 1970, 28 Cowstt~s BT, LawtxlR PP A tensitive method for the determination of carboxyhaemoglobin in a fu,ger prick sample of blood. Br J Ind %ted 22:139-13 3, 1965 KsssteR G, LeoeatR H: Fluoromevie measurement of -iglycendes. !+ Automation in Analvtical Chcmacry, Techntcon Symposia 1963 (Skegss LT, ed. ). New t'oric, \tediad, 1965, pp 341-345 HowavsectR F, Rvssrato A8: An inbred line of Svr an hamaterf with frequent spontaneow adrenal tumon. Caocer Res 30 305-308, 1970 Weot.LCr GW: Tumors of the adrenal cortex. !n C ba Foundation on Endrocrlnology. 12. Hormone Produc- tion in Endocrine Tumoun (tvolstenholme GE. O'Connor ' f, edt.l. Boston, Little Brown & Co., 1958, Pp 122-136 DoNrevwstt W: Experimental invesdsations on the erfeet of c;garette smoke inhalation on err.lil '.s5ora*ory aainalt /a Inhalatton Curenogenesu , Har.na MG Jr. Nettesham P, Gilbert JR, eds.l. .>EC Symp ienes \o. 18, 1970, pp 389-411 Hea.cto K~f: [nducuon of olfactorv -euroeo the!ui tumors in Svnan hamatess by diethylaisysa:rune. Cancer Il 11i-121, 1964 MeCORMIei A, Nteecotsov MJ, Bartes NfA, et al. Nitro- samtna in c garctte smoke condensate. Nature ;\ew Biol) 24i:237-238, 1973 's) ,6) (7) l B) '9) W 12) i .~- ~ 11 t Y i..N I R 1 1 f ? 042ef L..9 ..,.7t

tg 0 C.. • N . , ~ -_. . & F _ . _. /'. . ~_~--- . Ftotfas I.-Latyns of male 810 I S 16 harrato exposed to cigarette tmoke for 71 week.. Epttbelium thows m+aamal tluckeaa .You promr,aeot, regular layer of baaal cetla. Henucoeylin and eoua (H & E). X 800 Ftotns 2.-Hyyerplaaia in laryns of male BIO 97 ;0 !harroter exposed to smoks Wr 60 wee4a. Yar# moderitely thickened epiderr rtuai+aaUy aeypieal nuelei, and nuet baW iaver H & E. x E00 Ftotns 7.-Foe:al hyperplaaia in larvn: of Tale 810 15 16 bannter exposed to .moke for 73 weeks. .You .:.arkrdJy atyp cal auc and iatacn basal layv. H & E. x 900 FteCns C-Earlybasal cell hyperacav,rv n'arvne :f male 810 IS 16 haanter exposed to+moke foe ! 70 -'u .Y,u th:cY cptchel . with nanovw aone of wpernual keratLn,rauon Downqrowtlt of basal cella ~nth matouc acu"cy and wrr.e oudear arvpca; hu..e, normal oeteotauaf of cellb fauly weJl tr+unta~ned H & E. X 400 Ftouws 5.-Early basal cell hvDeracu•irv -n 'arvne of male BfO 97 20 hanuter exposed to imoke for 51 .eeki B.ual laver fo!ne- ^ ureBular but raL iotact. .You atvpical n~c.o ano aonorrrul keeauowuon tn deep ceU ae n fAC. H & E. x 300 Fiet.is 6.-`tarked ba.aW cell hyperacn-rv n'arvnt of male 810 13.16 huratrr exposed to smoke fcr 't2 weeta 6e.ere hvp~ keratoaif and aeanthaaa wuh nuclear aevpia. pan cularly tn the baul agim. .You re6ulal polanaat o0 of b.ual celh .n ae cdl oeata. H & E. X 250 1152 BERNIELD, HOMBL'4C?R, •ND RtaiF[T_C L' TR 1-If 7 04^'.-. 2 64

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Ftovas 10.-L,aryns of male 810 15 16 hamrter e:poted to tmoke for 91 weelo. (Juwra ofatypieal ep,:DeLal cub leep m ttro:= +uggest.lymphatic invauoo. H & E. X 400 Fzctru 11.-Lsr;e paptiloma nearly occlud,nS larvrnu of maJe BIO 87 20 0 hamryer e:po.ed to.moke for n -eeLS H t E. x 50 Ftccits 1?.-PspJloma of larynx from maJt 810 87 20 hamrtQ exposed to emote for 63 weela. Xwe a.e.,doep,anclwm,tous SrpQ- plaaia of covenag eptthdium. H & E. x;00 Ftctas I7.-Early tquamoui metaplat,a nmucui•secreung epit6elium of Larynx io male BIO 87 20 ~-a-wer eapo.eC ;o +rr.cac lor 86 weeka. H & E. x 800 1154 BLRIHRLD, HONalllc.tR, LND RCSStfE-:) • • - . - - . - •~ Vb- V Y\, .r. • • -VIwww_• - - -* .... CTR I IN V. 4i,., i! 66

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. FicU.a I8.-Pocts af Iquamoas meuplaos ia broocbial epithdium of male 810 15.16 bsmsrer expoaed to tmoke foe 92 weelu Neis ili8bt arocisujd cbrooic La6ammauoe aad dJated lympbauc. H Et E. X 400 Fictzs I9.-Papilloau ariains u rracbeal bJurcaum Ln male BIO 87.20 hamaer e:poaed to unoke for 78 wetlo. Geaioo parauli ob.uvcujd tracheal lumeu. H i E. x 50 Ficcu 20.-Lsrte papdlloma of broocMal onM in auk BIO 87 20 buoate e:po.ed to tmoke fa 82 weeh H S Ir X IS 1156 sRRNRLD, AOHIVAC><lt, AYD RUSSPSL.7 \..a' T1'`tr ! 1! 7 042268

M -)-) ~ ~. " 73. 2 F,ctxt :I.-.tdenoid c.+tac tumas of eawphar7ms in ma]e H1O I S:6 h.rdter eapa.ed to amoke far 70 weeis. No areae of icYauoa or dutant rutaatatn wae fouad. H & E. X 50 : ct tt 2?.-Su.or..atow tumor of naaopYaryn: in mak B1O I S i5 hurwtu arpo.ed to tmo~ke for 73 weeb. .~eu aliated rop rator~ ep~tCelium abo%e tu:-.or. H& E. TOOX -:ctat :7.-Pulr:onar% r-..etauaru from nuopharynReol tumor 0o.+o a rsura 22. H & L x 800 1157 OER.\fZLD, HONDL'RCER, A%D RUSSl1ZLD 4 I r 1~ t T1'` F t 1 0422 LJt F